The Control of Phosphate Exeretion in Uremia

Journal of Clinical Investigation Vol. 45, No. 5, 1966

The Control of Phosphate Exeretion in Uremia *

E. SLATOPOLSKY, L. GRADOWSKA, C. KASHEMSANT, R. KELTNER, C. MANLEY, AND N. S. BRICKER t

(From the Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Mo.)

The patterns of phosphate excretion in man with advancing chronic renal disease are well established. Although phosphate clearance decreases with time, it falls proportionately less than glomerular filtration rate, and the ratio of phosphate clearance to GFR increases as the disease advances (1). Thus the average rate of phosphate excretion per residual nephron increases as the nephron population diminishes, and the onset of hyperphosphatemia thereby is delayed. The explanation for this sequence is of considerable theoretical interest. The major possibilities are two: 1) The change could reflect the operation of a control system geared either to maintain external phosphate balance or to maintain plasma phosphate concentrations constant; 2) the relative phosphaturia per nephron could be a consequence of uremia or of the abnormalities in residual nephrons or both. These studies represent an attempt to distinguish between these two interpretations using the dog with intrinsic renal disease as the experimental model. The experiments also were designed to delineate the general characteristics of a control system, should one exist.

Methods

A total of 80 experiments was performed on 30 female mongrel dogs ranging in weight from 12 to 20 kg. The animals were fed standard dog chow, and supplementary horsemeat was given to assure a daily phos-

* Submitted for publication December 13, 1965; accepted January 12, 1966.

Supported in part by research grants AM-02667 and AM-09976 from the U. S. Public Health Service and by U. S. Public Health Service graduate training grant Ti AM-5248.

Presented at the National Meeting of the American Federation for Clinical Research, Atlantic City, N. J. An abstract has been published (Clin. Res. 1965, 13, 315).

t Career Research Award, U. S. Public Health Service. Address requests for reprints to Dr. Neal S. Bricker, Dept. of Internal Medicine, Washington University School of Medicine, St. Louis, Mo. 63110.

phate intake of at least 0.5 g. A preliminary bladdersplitting operation was performed to permit the quantitative collection of urine from the individual kidneys without recourse to ureteral catheterization (2). Thereafter, unilateral pyelonephritis was induced by a technique described previously (3). In five dogs, the diseased kidney was studied in the presence of the control kidney, and the functions of the two organs were com-

pared. These experiments were similar in design to those described in a previous publication (4) and were performed to verify the previous results in the present animals. In 27 dogs, the control kidneys were removed to permit investigation of the diseased kidneys under environmental conditions varying from moderate azotemia

to severe uremia. Three groups of animals were subjected to special

experimental maneuvers. In six dogs, GFR was reduced during clearance measurements either by con-

striction of the renal artery of the diseased kidney or by graded phlebotomy. Arterial constriction was accomplished with an arterial clamp that was placed about the renal artery just before initiation of clearance measurements. In six dogs, phosphate levels in the plasma were lowered by administration of aluminum carbonate gel by stomach tube for 3 days. A total of 150 ml per day was given in divided doses. Experiments were performed before and after this phosphate-depleting procedure. Finally, in eight dogs, thyroparathyroidectomy was performed to observe the effects of eliminating parathyroid hormone activity on phosphate excretion. Removal of parathyroid tissue was judged to be complete only if the animals became hypocalcemic and developed clinical manifestations of tetany. Seven of the eight dogs satisfied these criteria.

With the exception of the renal arterial constriction experiments, all clearance measurements were performed with the animals in the unanesthetized state. In most experiments, GFR was measured by the exogenous creatinine clearance. In the renal arterial constriction experiments inulin clearance was used to measure GFR, and in the prolonged phlebotomy experiments, GFR was estimated by endogenous creatinine clearance. Creatinine was measured by the method of Bonsnes and Taussky (5), inulin by the method of Roe, Epstein, and Goldstein (6), and phosphate by the method of Gomori (7). Plasma urea nitrogen levels were determined manometrically according to the method of Van Slyke and Kugel (8), and serum calcium concentrations were estimated by flame photometry. Additional details of the experimental techniques have been presented previously (3).

672

CONTROL OF PHOSPHATE EXCRETION IN UREMIA

673

Results

TABLE II

Summary of studies performed on 27 dogs with control kidneys

It is conventional to describe phosphate excre- removed and diseased kidneys providing the only source

tion in terms of the apparent tubular reabsorption

of renal function*

of phosphate or TRP.1 Although this term is a valid expression for the percentage of filtered phosphate reabsorbed only if there is no tubular secretion of phosphate, the interpretations of the present experiments would not be modified sub-

Mean value

GFR ml/min

14.5

PUN

mg/

100 ml

63.6

PPO4

mg/

100 ml

6.5

TRP

70

48.9

stantively if secretion of phosphate occurred.

SD

i 7.7 i12.3 ?2.2 A14.3

In Table I, data are shown for the five animals

that were studied with a control kidney in situ.

* GFR = glomerular filtration rate; PUN = plasma urea nitrogen. Other terms are defined in the footnote to

Values for the diseased kidneys are compared Table I.

with those for the contralateral control organs that

plasma urea nitrogen concentrations ranged from

TABLE I

23 to 150 mg per 100 ml and averaged 63.6 mg

Comparison of phosphate excretion in diseased and contralateral control kidneys*

per 100 ml for the group. The mean value for plasma phosphate concentrations was 6.5 mg per

100 ml with a range of 4.0 to 13.9. In contrast to

CCr

TRP

the animals in which a normal control kidney con-

Dog

Exp. Cont.

PPo4

Exp. Cont.

tributed to renal function, TRP was markedly

ml/min

mg/

100 ml

%

depressed, averaging 48.9%7o for the 27 dogs.

1

8.8 51.9 3.2 94.8 89.6 The range of TRP values was from 27.7 to 79.0%;

2 3

16.3 40.1 27.7 43.8

4.0 4.3

95.8 97.1 94.9 92.7

thus in all 27 dogs, TRP values were lower than

4

4.6 66.7 4.2 93.3 90.0

5

24.0 64.2 5.0 85.0 87.3

REMOVA.L OF

Mean value 16.3 53.3 4.1 92.8 91.3

SD ? 9.8 ? 11.9 ?0.2 i 4.4 i 3.8

U

GFR ml4min6

CONTROL KIDNEY

0- - .

0

_S

* All results are the average of three or more clearance periods in this and succeeding Tables. Ccr = creatinine clearance; Ppo4 = plasma phosphate concentration; TRP = tubular reabsorption of phosphate; exp. = experimental (i.e., diseased) kidney; cont. = contralateral control kidney.

0----i

10

PPO048

mgl

I'%

/

6-

were free of disease. In relation to the control

kidneys, GFR for the diseased organs was reduced

by from 27 to 93%. TRP averaged 92.8%o for

100

the diseased kidneys and 91.3%o for the control

organs. These values are not significantly different (p > 0.50). The lowest value for TRP in

TRP

60 -

any kidney was 85%o, and values for eight of the

40 -

ten kidneys were 89%o or greater. Table II summarizes the results from the 27

dogs in which experiments were performed after the control kidneys had been removed and the diseased kidneys provided the only source of renal function. GFR averaged 14.5 ml per minute

20 .

*.

0 Z4

5

TIME IN DAYS

FIG. 1. SEQUENTIAL CHANGES EVOKED BY REMOVAL OF

THE CONTROL KIDNEY IN A DOG WITH SEVERE UNILATERAL

PYELONEPHRITIS. The initial studies were performed before removal of the control kidney. Values for the

with a range of 2.7 to 30.8 ml per minute. The control kidney were as follows: glomerular filtration rate

(GFR) = 66.7 ml per minute; tubular reabsorption of

1 TRP = (1- Cpo4/GFR) X 100,- where Cm = phos- phosphate (TRP) = 90%. Ppo, = plasma phosphate con-

phate clearance.

centration.

674

SLATOPOLSKY, GRADOWSKA, KASHEMSANT, KELTNER, MANLEY, AND BRICKER

TABLE III

The effects of decreasing GFR on Cpo4 and TRP of the

diseased kidney*

Clearance Dog period

Ccr Cin PPo4 CPO4 TRPt

ml/min ml/ min

Constriction of renal artery

A 1-3 (control) 16.9 18.7

4

8.4 8.6

5

13.2 13.3

6

15.5 16.2

7

6.9 6.9

8

7.1 7.4

9

7.8 8.1

B 1-3 (control) 22.8 23.0

4

12.3 12.4

5

12.4 14.4

6

12.5 15.4

C 1-3 (control) 14.3 11.6

4

13.7 1 1.5

5

10.5 10.1

6

9.7 9.3

7

8.7 7.6

Phlebotomy

D 1-3 (control) 6.28

4

5.31

S

5.03

6

4.60

7

3.20

8

2.75

9

1.78

10

1.45

11

0.64

E 1-3 (control) 21.6

4

19.5

5

16.1

6

15.8

7

15.1

8

10.7

F 1-3 (control) 1.80

4

1.68

5

1.36

6

1.32

7

1.19

8

0.86

mg/ ml/min % 100 ml

5.4

7.1 62.0

5.1 2.7 68.6

5.0 3.6 72.9

5.1 4.2 74.1

5.6 2.2 68.1

5.8 2.4 67.6

5.6 2.8 65.4

5.63 12.9 44.0 5.60 7.9 36.3 5.60 8.3 42.4 5.60 8.2 46.8

5.4 6.6 43.0 4.3 4.79 58.0 4.9 2.66 74.0 5.5 3.50 62.4 6.1 3.70 51.0

12.0 4.26 33.0 11.4 3.76 29.2 11.8 3.44 31.6 11.8 3.02 34.0 11.3 2.16 32.5 11.3 1.80 34.6 12.8 1.01 44.3 13.0 0.82 43.0 13.3 0.40 37.5

5.6 7.92 63.0 5.3 7.75 60.3 5.2 5.02 68.8 5.3 5.01 68.3 5.0 4.59 69.6 4.3 2.90 72.9

15.2 1.51 16.0 16.1 1.35 19.7 15.9 1.11 19.4 16.8 1.-06 19.7 16.9 0.92 22.7 16.8 0.73 15.0

* Three control clearance periods were obtained before either renal arterial constriction or phlebotomy was initiated. In the phlebotomy experiments no infusions were employed, and GFR was approximated with endogenous clearance. In the renal arterial constriction experiments inulin clearance was used to measure GFR. Endogenous creatinine values were also determined in these experiments, and the values are included for comparison with the inulin clearances. The priming and sustaining infusions of inulin were calculated to achieve plasma inulin concentrations of approximately 25 mg per 100 ml. The clearance periods ranged from 20 to 60 minutes in duration. CIn = inulin clearance; CPO4 = phosphate clearance; other terms are defined in Table I.

t Calculation using CIn in the renal arterial constriction experiments.

85 %, the minimal value recorded in Table I for the nonuremic animals.

The sequential changes evoked by the removal of the control kidney are depicted graphically in Figure 1 for an animal with severe unilateral pyelonephritis. The initial studies were performed 6 weeks after disease was induced in the experimental kidney, but before removal of the control

kidney. The GFR for the diseased kidney was 4.6 ml per minute. After nephrectomy, GFR increased over the 8-day period of study to approximately twice its initial value. The plasma phosphate concentrations increased strikingly from the

prenephrectomy value of 4.1 mg per 100 ml to 11

mg per 100 ml; but the peak was reached on the

fourth day, and on the eighth day, the value had decreased to 6.7 mg per 100 ml. TRP was 93%o in the initial study. Two days after nephrectomy, the value was 80%o. Four days after nephrectomy, it was 36%o.. On the eighth day, the TRP was

299.

The increase in GFR depicted in Figure 1 is a characteristic occurrence in the diseased kidney of the dog after the contralateral control kidney is removed (3). To evaluate the possibility that hyperfiltration was responsible for the depression of TRP, we assessed the effects of experimental reduction in GFR on phosphate excretion. In three animals GFR was reduced by constricting the renal artery; in another three animals GFR was diminished by graded phlebotomy carried out over periods ranging from 4 to 6 hours. In both groups three control periods were obtained before reducing GFR. The data are presented in Table III. Regardless of the degree of reduction of GFR (the maximal reduction varied from 27 to 90%o), TRP was not restored to a normal

TABLE IV

The effects of decreasing plasma phosphate concentrations on phosphate excretion*

Experiment PPO4 PCa CCr FL Cpo4 TRP

mg/ mg/ ml/min mg/,'min ml/ %

100 ml 100 ml

min

Pre

4.9 9.7 7.7 0.38 4.6 40.3

I

Post 2.5 10.2 8.4 0.21 4.0 52.4

Pre

7.2 8.6 10.4 0.75 7.9 24.0

2

Post 4.5 10.0 13.7 0.62 7.7 43.8

Pre

5.9 9.4 11.4 0.67 5.4 52.6

3

Post 4.1 11.8 13.7 0.56 2.1 84.7

Pre 13.9 9.2 8.3 1.15 6.9 16.9

4

Post 5.3 10.0 6.5 0.34 5.3 18.5

Pre

4.9 8.7 16.7 0.82 8.5 49.1

5

Post Pre 6 Post

3.9 10.8 14.7 0.57 3.1 78.9 5.0 8.5 20.0 1.00 8.8 56.0 3.8 10.0 22.7 0.86 6.7 70.5

Pre Mean

Post

7.0 9.0 12.4 0.80 7.0 39.8 4.0 10.5 13.3 0.53 4.8 58.1

* Pre and 'post refer to the studies performed before and after aluminum carbonate gel administration. No Donnan correction was applied in calculating the filtered load of phosphate (FL). Pc,, = plasma calcium concentration.

CONTROL OF PHOSPHATE EXCRETION IN UREMIA

675

range, and in most animals the increments were ectomized animals, 250 U of a parathyroid hor-

modest. The highest value achieved for TRP was mone preparation 2 was administered intrave-

74.1 in dog A. In dog D, although creatinine nously, and three additional 20-minute clearance

clearance was reduced slowly over a 6-hour pe- periods were obtained. Under the influence of

riod from 6.3 ml per minute to 0.64 tnl per min- exogenous parathyroid hormone, the TRP values

ute, TRP increased only from 33%o to a maximal decreased markedly in all animals, and the mean

value of 44.3%o.

value for the group closely approximated the pre-

The effects of decreasing the filtered load of parathyroidectomy level (i.e., 54.0% vs. 55.1%o).

phosphate by lowering the serum concentration

of phosphate are shown in Table IV. Studies

Discussion

were performed before and immediately after a 3-day period of aluminum carbonate gel administration. The decrease in plasma phosphate concentrations ranged from 1.0 to 8.6 mg per 100 ml, and filtered phosphate decreased by an average of 34%o. A reciprocal increase in plasma calcium levels was observed in each of the six animals. In one animal (experiment 3), the TRP increased from 52.6 to 84.7, and in another (experiment 5) the value rose from 49.1 to 78.9. However, in the other four dogs, the increments were small, and for the group the mean value for TRP in-

creased from 39.8% to 58.1%.

Table V presents the data obtained from the seven animals studied before and after thyropara-

thyroidectomy. TRP averaged 55.1% (range 41 to 78.2%o) before parathyroidectomy. The values obtained after the surgical induction of hypoparathyroidism were increased strikingly. In three dogs the values exceeded 90%, and in one of these (dog 7) TRP averaged 98%o. The mean value for the seven dogs was 88.9%o. After completion of

When chronic renal disease exists in only one kidney and there is a contralateral kidney present that is free of disease, the total number of nephrons is not greatly diminished. In this setting, values for TRP in the chronically diseased

kidney of the dog characteristically exceed 75%

and often are in excess of 85% [(4) and Table I]. Moreover, the values for the diseased kidneys are closely comparable to those of the contralateral organs regardless of the severity of the unilaterial lesion. However, when the nephron population was diminished markedly by removing the normal kidney, the TRP in the residual nephrons of the diseased organs decreased strikingly, and the pattern characteristic of uremic man (1) was reproduced in the uremic dog (Table II). This decrease in TRP implies that the average rate of phosphate excretion per nephron increased. If such a change in phosphate excretion is initiated and sustained by a control mechanism, rather than by the fortuitous emergence of a defect in phos-

three to four clearance periods in the parathyroid- 2 Parathormone, Eli Lilly, Indianapolis, Ind.

TABLE V

The effects of thyroparathyroidectomy and PTH infusion on PO, excretion

Dog

1 2 3 4 5 6 7

Mean SD

Before thyroparathyroidectomy

GFR PPO4 Pc&

TRP

mil/min mg/ mg/

%

100 ml 100 ml

7.6 7.5 10.0 51.4

7.7 4.4 9.7 41.0

11.4 5.9 9.4 52.6

16.4 4.9

8.8 49.1

20.5 4.6 9.1 47.3

30.7 4.3 8.7 65.8

30.8 6.2

9.8 78.2

17.9 5.4 9.4 55.1 ? 9.9 i1.2 i 0.5 ? 12.9

GFR

ml/min

5.0 12.6 12.0 14.4 14.8 41.5 25.6

18.0 412.0

After thyroparathyroidectomy

Before PTH

After PTH*

PPO4

Pca

TRP

GFR PpO4 TRP

mg/ mg/

%

ml/min mg/

%

100 ml 100 ml

100 ml

5.9 7.8 93.0

6.8 5.5 48.7

3.7 6.4 93.9

11.2 3.5 75.0

6.1 5.6 89.0

16.1 4.1 58.9

4.7 6.8 73.8

17.0 4.7 41.2

5.6 4.4 88.6

19.0 5.0 46.8

5.4 7.7 85.9

41.6 4.1 47.4

5.6 7.8 98.0

26.8 4.5 59.7

5.3 6.6 88.9

?0.8 ?1.3 ? 7.8

19.8 4.5 54.0 i11.5 ?0.2 ?10.2

* 250 U of parathyroid hormone (PTH) was administered intravenously in a single injection.

676

SLATOPOLSKY, GRADOWSKA, KASHEMSANT, KELTNER, MANLEY, AND BRICKER

phate reabsorption, three different factors may be impairment in the residual nephrons seems very

considered as possible effector mechanisms.

unlikely. The fact that TRP values in the diseased

1) Since removal of the normal kidney in this kidneys were closely comparable to those of the

model is associated with an adaptive increase in contralateral kidneys (Table I) would speak

GFR in the diseased kidney (3), hyperfiltration against a fandom defect in phosphate transport

could underlie the relative phosphaturia.

in the nephrons of the diseased organs, and the

2) Plasma phosphate concentrations were ele- fact that the absolute values for TRP were 85%o or

vated in many of the uremic dogs. The attend- greater in these same animals would speak against

ant increase in the filtered load of phosphate could a major defect in phosphate reabsorption. More

contribute to the phosphaturia.

compelling evidence is found in the response to

3) Secondary hyperparathyroidism, which characteristically occurs in uremia (9-11), could play the dominant role in the altered patterns of phosphate excretion.

The role of hyperfiltration was examined by reducing GFR experimentally. Reduction in values by as much as 90%, however, generally was associated with only a moderate increase in TRP, and in no instance were values restored to a normal range. Experimental reduction in plasma phosphate concentrations toward normal (and in some animals to below normal levels) evoked an increase in TRP of varying magnitude, but in only one instance (dog 3) was a value approaching the normal range reached. On the other hand, the

thyroparathyroidectomy in the uremic dogs. In three animals, TRP values rose to levels in excess of 90%o, and in one animal the value was

98%.

It is concluded that there is a control system that serves to modulate phosphate excretion in advancing chronic renal disease. The afferent limb of this system has not been defined by these studies, but the evidence presented supports the view that parathyroid hormone is the prepotent constituent of the efferent limb, with hyperfiltration of the residual nephrons playing a subsidiary role. Hyperphosphatemia, when present, contributes to an increase in phosphate excretion per nephron.

results of surgical removal of the parathyroid glands were dramatic. In the seven animals stud-

Summary

ied, before and after thyroparathyroidectomy, the These studies were designed to define the basis

mean value for TRP increased from 55.1% to of the change in the patterns of phosphate excre-

88.9%. This postparathyroidectomy value of tion that occurs in renal insufficiency. Charac-

88.9% compares quite favorably with the mean teristically, phosphate clearance decreases propor-

value of 92.8% obtained in the diseased kidneys tionately less than glomerular filtration rate

of the five nonuremic dogs studied before removal (GFR); hence TRP, a derived expression for the

of the control organs. The rise in TRP, more- apparent net tubular reabsorption of phosphate,

over, was not attended by a decrease in GFR; in- falls. In animals with unilateral renal disease and

deed, in two of the seven dogs (dogs 2 and 6, Ta- a contralateral control kidney, TRP values were

ble V) GFR increased appreciably after parathy- not decreased in the diseased kidneys, and there

roidectomy. Furthermore, in five of the seven was equality of values in the two kidneys. How-

postparathyroidectomy studies, plasma phosphate ever, in 27 dogs in which the diseased kidney pro-

concentrations were 5.4 mg per 100 ml or greater. vided the only source of renal function, the TRP

Thus, the rise in TRP occurred in the presence of was decreased to a mean value of 48.9%. In seek-

persisting hyperfiltration and hyperphosphatemia. ing the basis for this change, we considered three

The composite data thus point to the parathyroid factors: 1) hyperfiltration in the residual neph-

hormone as the principal effector mechanism in a rons, 2) hyperphosphatemia, and 3) secondary

control system regulating phosphate homeostasis in hyperparathyroidism.

uremia. The response to parathyroid hormone Neither experimental reduction of GFR by as

administration in the parathyroidectomized dogs much as 90%, nor lowering of plasma phosphate

(Table V) adds weight to this interpretation. concentrations, regularly resulted in marked in-

That the low TRP values observed in the azo- crements in TRP. In contrast, thyroparathyroid-

temic and uremic animals resulted from functional ectomy was associated with an increase in TRP

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